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Page 5 macrophages and the numbers of CD4 cells remain stable but decreased an individual from R5 to R4 is the precursor to developing immune deficiency The key is the ping pong effect among infection by the R5 strain, clinical latency, gradual mutation to R4 strain infecting naÔve T cells, loss of the epitope war*, loss of the ability to control viral replication, and development of AIDS *epitope war: battle of epitopes, typically those recognized by antibodies or T cells; the interaction between the expressed genome of HIV and our immune systemís ability to recognize and control it Acute HIV-1 Infection: HIV is controlled by the immune system but only for a period of time Clinical: Typical viral infection At the end of the virus Headache, retro-orbital pain, myalgias, pharyngitis, fever Nonpruritic maculopapular rash in first 1-3 weeks Adenopathy and malaise may last for several months or may not even be noticed Transient thrombocytopenia and CD4 T cell lymphopenia Rapid appearance of marked viremia with R5 strain infecting monocytes and memory CD4 T cells Results in acute CD4 T-cell lymphopenia Integration into memory CD4 T cells provides a long-lived reservoir where HIV can remain latent The virus is brilliantly clever in utilizing features of the immune system Structurally the initial virus strain has no, or very limited diversity, so infection apparently occurs only by one strain, even though what is transmitted from one person might be hundreds of different strains Anti HIV Immune Response With onset of CD8 response viremia falls from5X10 6 /mL to <10 4 /mL, sometimes undetectable CD4 count rises from400 to 800/ĶL A key concept that isnít fully understood: Degree of viral suppression and return of CD4 levels (set point) varies and correlates with the length of the asymptomatic period; there have been attempts to treat with retrovirals and other means to manipulate the set point HIV species begin to diversify, viral variants appear reflecting successful attempts to escape the suppression of CD8 response, body brings in another CD8 type (concept of epitope war) The virus mainly persists in monocytes and macrophages 5 Page 6 Experimental infection with SIV (Simian) of intact and CD8 depleted monkeys illustrates role of CD8 T cells in controlling viremia CD8 Response to HIV-1 Establishes asymptomatic phase of infection CD8 responds to HIV peptides by activation, clonal expansion, and differentiation to effectors 2 Critical Events: 1. Specific lysis of HIV-infected target cells (macrophages and CD4 cells) via perforin pathway and/or apoptosis via upregulation of fas ligand 2. Strong inhibition of viral infectivity by release of chemokines (MIP-1a/Ŗ, RANTES) that bind to CCR5 and block coreceptor dependent entry of R5 HIV-1 Lastly, release of IFN-? and secondarily TNF-a ?? LTR-driven transcription Excessive anti HIV CD8 response may result in diffuse infiltrative lymphocytosis syndrome (DILS) stimulating Sjogrenís syndrome T cell infiltration leads to dry eyes, loss of salivary gland secretions Disabling autoimmune disease with autoantibodies resembling those found in lupus patients DILS is usually associated with long term non-progression and a favorable outlook, but it is also associated with a type of B cell lymphoma that occurs early in the course of HIV infection, reflecting chronic cell stimulation (begin in lacrimal gland or salivary gland) Thwarted Immunosurveillance No expression of viral peptides Also inaccessible to Rx 6 Reasons for failure of CD8 cells to totally eliminate HIV-1 1. HIV may integrate into a region of the heterochromatin (e.g. in memory CD4 T cell) where it remains undetected and inaccessible to therapy for as long as that CD4 T cell is quiescent; activation of CD4 cell leads to reexpression of HIV 2. Nef and vpu diminish MHC class I expression, thus avoiding infection surveillance, especially when in monocytes Extra credit: Nef is particularly clever since it decreases HLA-A and HLA-B, but not HLA-C and HLA-E, thus avoiding most NK cell surveillance; what goes on in the placenta 3. Dendritic cells are used as a Trojan Horse Immature DCs typically located in the submucosa express a C-type lectin CD-SIGN HIV-1 envelope binds to CD-SIGN with high affinity The virions are internalized and remain in acidic endosomal compartments while the DC matures Intact infectious virions are reexpressed on the surface when the CD enters the lymph node Page 7 Why donít antibodies work? It takes too long for antibodies specific for a particular strain to develop The virus is evolving at a rate too great for the immune system to keep up with Immune Responses in Asymptomatic Phase: Depends on a relatively few CD8 clones Maintenance of <5-20 CD8 expanded memory/effector CTL clones, each comprising 1-5% of CD8 repertoire Clones each recognize different HIV peptides, great individual variation in number and particular peptide recognized Many clones = generally good outlook for long asymptomatic period ( 12 year), few clones = rapid progression of HIV infection (< 2 years) The number of clones and survival duration correlates with the viral set point established in the acute infection; set point reflects the adequacy of a personís immune system to respond to HIV Long term non progresors Subset of infected individuals that remain asymptomatic for 12 years Particular HLA types, e.g. HLA-B27, B57 Low levels of plasma virions, CD4 counts 500/ĶL High CD8 counts, maybe 3000/ ĶL CTL response is against critical conserved region of HIV gag, env, pol that cannot readily be mutated without loss of viral function; This appears to be the key factor High chemokine release (RANTES, MIP) The particular peptide that is recognized in HIV by cytotoxic CD8 cells is critically important to whether the infection will be controlled If the recognized peptide encodes a region that is essential for HIV function, any mutation in that site will be lethal for the virus; for this to occur to conditions must be met: 1) The correct peptide must be presented. The individualís class I MHC alleles are the major determinant of which peptide is recognized. They determine the particular peptides that are bound and presented 2) The peptide must be recognized by a T cell clone. Not all bound peptides are equivalently recognized by T cell clones in the repertoire. Only a few bound peptides are immunodominant, and readily recognized. The T cell ligand is a combination of peptide and class I MHC, and it demonstrates the importance of polymorphism in the HLA molecule The environment formed by peptide binding properties of MHC molecules influences evolution of the HIV infection. HLA alleles influence the number of peptides in a protein that can be recognized (e.g. HIV envelope protein) Allele: HLA-B*27052 HLA-B*3501 HLA-B*0702 Motif: XRXXXXXX[KRYL] XPXXXXXXY XPXXXXXXL Each allele is able to bind a number of different peptides 7 Page 8 Basis of outcome with HLA type HLA B35 Rapid Progression HLA B27 Slow progression PXXXXXY peptides recognized if any are in noncritical parts of HIV genome permitting mutations in MHC anchor residues Peptides are weak stimulators Rapid viral replication and evolution not restrained RXXXXXX[KRYL] peptides recognized are often in critical parts of HIV genome and mutations not permitted in MHC anchor or TCR recognition residues Peptides give strong stimulation Viral replication and evolution greatly slowed Immune Response Asymptomatic phase: Shifiting immunodominance in epitope war Near end of asymptomatic period Usually recurrent pattern of HIV escape from immunodominant CTL effect by mutation followed by regain of CD8 control via next HIV peptide that can be presented by MHC I and recognized by TCR in hierarcy of HIV peptide immunodomiance During the progression of the infection in a person a huge number (swarm) of mutant forms arise (quasispecies) Ultimately return of high viral levels, 10 6 /mL Rate of viral infection and potential mutations increases. Definitive viral escape occurs when virus is no longer presented by MHC to available CD8 clones Continual generation of env mutations Selection against R5 variants by CD8 CCR5 chemokines that blocks infection is finally bypassed Change in cellular tropism by env mutations leads to R4 phenotype Enhanced R4 tropism leads to more significant impairment of naÔve CD4 compartment-This is the critical undoing of the immune response Loss of the epitope war : 1) Viral control lost 2) Mutation to different tropic strain Reasons for CD4 T cell loss in HIV infection: During asymptomatic phase and transition to AIDS, there is an accelerated loss in number of CD4 T cells Activation of large numbers of mature and naÔve CD4 cells by cytokines, etc during antiviral response (bystander activation) leads to loss of repertoire by physiologic apoptosis because T cells arenít activated by signal 1 and 2 but rather, by an inappropriate mechanism Thymic derangement results in failure to generate new naÔve CD4 T cells to repopulate repertoire CD8 T cell killing of infected CD4 T cells ACDD by NK cells, etc to infected CD4 T cells 8 Page 9 Another reason for CD4 loss CD4 activation initiates HIV replication HIV replication initiates CD4 activation T cell activation causes a marked increase in cyclin T1, NFAT and NF ? B This links viral expression to T cell activation AIDS is the Consequence of progressive CD4 loss: T cell immune function progressively deteriorates reflecting the central role of CD4 T cells Loss of antigen-specific clonal responses (in vitro proliferation and skin test to various antigens, including those from immunizations) Loss of ability to generate new CD8 responses Loss of Mixed Lymphocyte Culture responsiveness Loss of PHA responsiveness Clinically, there is a hierarchy of infections developing as immune deficiency progresses to frank AIDS reflect differing roles of CD4 T cells Candida (Thrush) Salmonella-microbial persistence (Reactive arthritis?) Mycobacterium tuberculosis reactivation, Cryptosporidium Activation of latent herpes zoster EBV reactivation and development of polyclonal lymphomas, Kaposiís sarcoma (HHV-8) Pneumocystis carinii Progressive cytomegalovirus infections, M. avium complex Why has an HIV virus vaccine failed? Immunization with rENV should, in theory, produce neutralizing antibodies and perhaps CD8 immunity But neutralizing antibodies induced by immunization fail to protect A live attenuated virus has not yet proved achievable For a CD8 vaccine one major issue is providing HIV peptides able to bind divergent MHC class I of a large proportion of the population The second larger issue is immense heterogeneity of HIV, need many immunodominant peptides directed to critical regions of viral genome because no cross protection Some strains, mainly R4 tropic have evolved to circumvent MHC presentation by some common alleles. With high numbers of infected individuals, there is increasing chance of infecting a person with the same HLA by a strain evolved to avoid immunosurveillance There still is hope in that 1) HIV is a disease that one neednít acquire, and 2) some people are long-term survivors (e.g. Nairobi prostitutes constitute a minority of people who are repetitively exposed to HIV but donít acquire it-their immune systems can respond to the virus) 9